Drugs for Congestive Heart Failure Cardiovascula r System Course William B. Jeffries, Ph.D. Room 570A Criss III, 280-4092 Email: [email protected] flap.creighton.edu Required reading: Katzung, 9 th ed. pp. 201- 215, 281-290 Digitalis Lanata
Dec 30, 2015
Drugs for Congestive Heart
Failure
Cardiovascular System Course
William B. Jeffries, Ph.D.Room 570A Criss III, 280-4092Email: [email protected]
flap.creighton.edu
Required reading: Katzung, 9th ed. pp. 201-215, 281-290
Digitalis Lanata
Compensatory Mechanisms in Heart Failure
• Mechanisms designed for acute loss in cardiac output
• Chronic activation of these mechanisms worsens heart failure
Potential Therapeutic Targets in Heart Failure
• Preload
• Afterload
• Contractility
• Remodeling
Positive Inotropic Agents
• Cardiac Glycosides
• Phosphodiesterase inhibitors
• -adrenoceptor agonists
Cardiac Glycosides
• digoxin • digitoxin • deslanoside • ouabain
Mechanism of Digitalis Action: Molecular
• Inhibition of Na/K ATPase
• blunting of Ca2+ extrusion
• Ca2+i
• sarcomere shortening
Effects on Cardiac Function
Three Types of Effects:• Mechanical Effects: Positive inotropy
– Caused by increased Ca2+ Availability
• Direct Electrophysiological Effects – Altered cellular action potential– Afterdepolarizations
• Indirect Electrophysiological Effects:– Mediated through increased vagal tone
and withdrawal of sympathetic tone
Direct Electrophysiological Effects:Cellular Action Potential
Afterdepolarizations
Parasympathomimetic Effects
• Vagus-mediated hyperpolarization of AV node. Leads to:– Decreased conduction velocity in the AV node – Increased effective refractory period in the AV
node– AV block (toxic concentrations)
Therapeutic Uses of Digitalis
• Congestive Heart Failure
• Atrial fibrillation
Overall Benefit of Digitalis to Myocardial Function
• cardiac output
• cardiac efficiency
• heart rate
• cardiac size
NO survival benefit
Administration
• Digoxin has a long enough half life (24-36 hr.) and high enough bioavailability to allow once daily dosing
• Digoxin has a large volume of distribution and dose must be based on lean body mass
• Increased cardiac performance can increase renal function and clearance of digoxin
• Eubacterium lentum
Adverse Effects
• Cardiac – AV block – Bradycardia – Ventricular extrasystole – Arrhythmias
• CNS
• GI
Therapeutic index is ~ 2!
Serum Electrolytes Affect Toxicity
• K+
– Digitalis competes for K binding at Na/K ATPase
– Hypokalemia: increase toxicity– Hyperkalemia: decrease toxicity
• Ca2+
– Hypercalcemia: increases toxicity
Phosphodiesterase Inhibitors
• amrinone
• milrinone
Mechanism of Action• inhibition of type III phosphodiesterase
intracellular cAMP activation of protein kinase A
o Ca2+ entry through L type Ca channels o increased Ca2+ sequestration by SR o Phosphorylation of MLCK
• cardiac output• peripheral vascular resistance• “Inamrinone”
Phosphodiesterase Inhibitors: Therapeutic Use
• short term support in advanced decompensated cardiac failure
• long term use not possible
Adverse Effects of Phosphodiesterase Inhibitors
• Cardiac arrhythmias
• GI: Nausea and vomiting
• Sudden death
-Adrenoceptor and Dopamine Receptor Agonists
• Dobutamine • Dopamine
Mechanism of Action: Dobutamine
• Stimulation of cardiac adrenoceptors: inotropy > chronotropy
• peripheral vasodilatation
• myocardial oxygen demand
Mechanism of Action: Dopamine
• Stimulation of peripheral postjunctional D1 and prejunctional D2 receptors
• Splanchnic and renal vasodilatation
Therapeutic Use
• Dobutamine: management of acute decompensated failure only
• Dopamine: restore renal blood in acute failure
Adverse Effects
• Dobutamine – Tolerance – Tachycardia
• Dopamine – Tachycardia – Arrhythmias – Peripheral vasoconstriction
ACE Inhibitors in Heart Failure
Therapeutic targets in heart failure
Mechanism of Action
• Afterload reduction
• Preload reduction
• Reduction of cardiac remodeling (hypertrophy)
• Withdrawal of sympathetic tone
ACE Inhibitors: Therapeutic Uses
• Drugs of choice in heart failure (with diuretics)
• Acute myocardial infarction
• ATII antagonists
Diuretics: Mechanism of Action in Heart Failure
• Preload reduction: reduction of excess plasma volume and edema fluid
• Afterload reduction: lowered blood pressure
• Reduction of facilitation of sympathetic nervous system
Vasodilators
• Mechanism of action: reduce preload and afterload
• Drugs used – Isosorbide dinitrate + Hydralazine
• Demonstrated survival benefit• Inferior to ACE inhibition
– Ca2+ channel blockers • No benefit in systolic failure• Use in diastolic failure?
– Alpha-1 adrenergic antagonists: • no proven benefit
– Neseritide
Nesiritide
• Recombinant B-type natriuretic peptide
• Mechanism of Action – Activates smooth muscle guanylyl cyclase– Dilatation of venous and arterial beds– Natriuresis/diuresis (but not in
decompensated heart failure)– Preload and afterload reduction– Reduced pulmonary capillary wedge
pressure– Reduced dyspnia
Nesiritide
• Approved in acute decompensated failure
• Off Label Use: Ambulatory heart failure
• Effects similar to nitrates
• Adverse effects: – hypotension (NO arrhythmias)
– Increased renal failure?
– Increased death rate?
See: Topol, NEJM 353:2 113-116, 2005
-Blockers in Heart Failure: Mechanism of Action
• Standard -blockers: – Reduction in damaging sympathetic
influences in the heart (tachycardia, arrhythmias, remodeling)
– inhibition of renin release
• Carvedilol: – Beta blockade effects– peripheral vasodilatation via 1-adrenoceptor
blockade
Aldosterone Antagonists• Rationale:
– Aldosterone promotes increased plasma volume, Increased serum K, and (possibly) hypertrophic effects on the heart
– Aldosterone inappropriately elevated in CHF (even after ACE inhibition)
– Thus, positive outcome if aldosterone effects on heart and kidney are prevented
• Evidence: Aldosterone antagonists have been shown to reduce mortality in CHF
• Available aldosterone antagonists– Spironolactone– Eplerenone
Spironolactone and Eplerenone
• Aldosterone antagonists, K-sparing diuretics• Effects in Heart Failure
– Potassium Sparing Diuretics• Mobilize edema fluid in heart failure• Prevent K loss caused by other diuretics (protection against
digitalis toxicity?)
– Reduction of cardiovascular remodeling
• Potential side effects– Hyperkalemia– Androgenic effects (spironolactone)– Gynecomastia (spironolactone)
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